1. Clin Med II Infectious Disease
Lecture II—Viral Diseases, part 2/3

2. Herpes Simplex Virus

3. What’s with all the numbers? Human Herpesviruses
HHV 1—Herpes Simplex Virus type 1
HHV 2—Herpes Simplex Virus type 2
HHV 3—Varicella Zoster Virus
HHV 4—Epstein-Barr Virus
HHV 5—Cytomegalovirus
HHV 6—Roseola Infantum
HHV 7—”The Multitasker”
Roseola, Seizures, Encephalitis, “helps” CMV in renal transplants
HHV 8—Kaposi sarcoma/primary effusion lymphoma

4. Herpes Simplex Virus HSV-1—oral HSV-2—genital
Risks—in text—black race, female gender, lower socioeconomic status, and high-risk sexual history
Asymptomatic shedding
HSV-2 and HIV—linked
HSV-2 increases risk of HIV HSV-2 reactivates more often in advanced HIV
HSV-2 suppression can decrease HIV-1 plasma level and genital tract shedding

5. Mucocutaneous HSV-1 HSV-1—mouth and oral cavity
”herpes labialis” or “gingivostomatitis”
Herpetic whitlow—painful digital lesions
Herpes gladiatorum—painful rash transmitted classically by sports contact
Frequent asymptomatic shedding—monthly or more
Vesiclesulcers (1-2 days)epithelialization (1-2 wks)
Recurrences--fewer lesions, labial, heal faster
Triggers—stress, fever, infection, sunlight, chemo, ???

6. Mucocutaneous HSV-1

7. Mucocutaneous HSV-1

8. Mucocutaneous HSV-1

9. Mucocutaneous HSV-2 Primarily involves genital tract
May affect perianal region, buttocks, upper thighs
Multiple, painful, small, grouped, vesicular lesions
Dysuria, cervicitis, urinary retention
Increased HSV-2 lesion rates—postpartum period and among women who have sex with women
HIV patients—proctitis and sacral lesions
extensive, ulcerating, weeping lesions
Drug-resistant isolates—large ulcerations, atypical lesions

10. Mucocutaneous HSV-2

11. Mucocutaneous HSV-2

12. Mucocutaneous HSV-2

13. Mucocutaneous HSV Diagnosis
Clinical
Standard—viral cultures of vesicular fluid or direct immunofluorescent antibody staining of lesions
Intranuclear inclusion bodies
Multinucleated giant cells on Tzanck smear or Calcofluor prep

14. Mucocutaneous HSV Treatment often not necessary in immunocompetent pts
Genital infection—oral agents—acyclovir, valacycloivr, famiciclovir
Primary—7-10 days and higher doses; Recurrent—1-3 days
Primary herpes labialis—oral antivirals as for primary genital
Recurrent herpes labialis—topical acyclovir and hyrocortisone, topical penciclovir, or oral antivirals
Immunocompromised—consider IV antivirals
Atypical isolates, large ulcerations, new lesions, poor response
Secondary prophylaxis—recurrent infections—daily oral antivirals

15. Ocular HSV Keratitis, Blepharitis, Keratoconjuncitvits
If epithelial—heal without vision impairment
If stroma involved— uveitis, scarring, blindness
Frequent recurrence
Second most common cause of acute retinal necrosis

16. Ocular HSV Branching (dendritic) ulcers on fluorescein stain
Treat with topical antivirals
Acute retinal necrosis—IV acyclovir or oral famciclovir
Topical steroids—may exacerbate
Long term treatment can reduce recurrences

17. Congenital/Neonatal HSV
HSV-1 and HSV-2
Congenital—organomegaly, bleeding, CNS abnormalities
Neonatal is more common than congenital
Highest risk—maternal infection in 3rd trimester
70% of infections are asymptomatic or unrecognized

18. Congenital/Neonatal HSV
Treat disseminated lesions with IV acyclovir for 2-3 weeks
Counseling with serologic screening should be offered to pregnant mothers
Maternal antenatal suppressive therapy with acyclovir at 36 weeks gestation
C-section for pregnant women with active genital lesions or prodromal symptoms

19. HSV and CNS Disease
HSV-1: HSV Encephalitis, may enhance Alzheimer disease
Encephalitis symptoms: flu-like prodrome, headache, fever, behavioral or speech disturbances, seizures
High mortality rate—untreated, presentation with coma
Does not occur disproportionately among immunocompromised
HSV-2: Meningitis (primary or recurrent)
Both HSV-1 and HSV-2: benign recurrent lymphocytic meningitis; mild, nonspecific neurologic symptoms

20. HSV Encephalitis and Recurrent Meningitis
CSF Pleocytosis common
HSV DNA PCR of CSF— rapid, sensitive, specific but can have up to 25% false negatives
MRI scanning—increased signal in temporal and frontal lobes
IV acyclovir q 8 hours for 10+ days if suspected HSV encephalitis
Long term neurologic sequelae are common

21. HSV Encephalitis

22. Other HSV Manifestations
Disseminated—immunosuppression, pregnancy
Bell’s Palsy—associated with HSV-1
Esophagitis—HSV-1; immunocompromised
Proctitis—primarily in men who have sex with men
Erythema multiforme—leading association with EM and SJS (along with medications)
Acute liver failure—1% of cases but 75% mortality
Lower respiratory tract—mechanically ventilated pts
HSV-1—perinephric abscess, febrile neutropenia, chronic urticaria, SLE-related esophagitis and enteritis, H. pylori- negative upper GI ulcers, atrial myxoma

23. HSV Prevention Antiviral suppressive therapy Counseling
Barrier precautions
Disclosure of partner status—50% decrease in HSV-2 transmission
Hand washing and glove/gown precautions
HSV-2 glycoprotein D vaccine is under development

24. Varicella Zoster Virus

25. Varicella Zoster Virus
Manifests as chickenpox (varicella) and shingles (zoster)
Varicella—typically in childhood; incubates days
Highly contagious— droplet inhalation or lesion contact
Zoster—up to 25% of population; increases with age

26. Varicella Fever and malaise Pruritic rash
Maculopapulesvesicles pustulescrusts
Multiple stages of eruption usually present simultaneously
“dew drop on rose petal”
Complications—secondary bacterial infection, pneumonitis, encephalitis—in 1%
More severe in older pts and immunocompromised

27. Zoster Mostly among adults Pain—severe—often precedes rash
Varicella-like lesions—usually in dermatomal distribution
Herpes Zoster Ophthalmicus—lesions on tip of nose, inner corner of eye, and root and side of the nose (Hutchinson sign)
Herpes Zoster Oticus—facial palsy, lesions of ear +/- TM involvement, vertigo, tinnitus, deafness (Ramsay Hunt syndrome)
Contact with varicella patients—not a risk factor

28. Herpes Zoster Ophthalmicus

29. Herpes Zoster Oticus

30. Varicella Zoster Virus
Diagnosis—usually clinical
Confirm with direct immunofluorescent antibody staining or PCR of scrapings from lesions
Multinucleated giant cells on Tzanck smear
Leukopenia and subclinical AST/ALT elevation
Thrombocytopenia
Varicella skin test and ELISPOT—VZV susceptibility

31. Varicella Complications
Secondary bacterial skin superinfections
Interstital VZV pneumonia
Neuro—cerebellar ataxia, encephalitis
Purpura fulminans—extremely rare
Liver—hepatitis, Reye’s syndrome
Pregnancy—
1st or 2nd trimesters, small risk of congenital malformations
3rd trimester, risk of disseminated disease

32. Zoster Complications
Postherpetic neuralgia—60-70% of pts >60 years old
Bacterial skin superinfections
Herpes zoster ophthalmicus or unilateral ophthalmoplegia
Cranial nerve involvement
Aseptic meningitis
Peripheral motor neuropathy
Transverse myelitis
Encephalitis
Acute cerebellitis
Stroke or vasculopathy
Acute retinal necrosis or progressive outer retinal necrosis

33. VZV Encephalitis

34. VZV—Treatment
General treatment measures—initial isolation; bed rest till afebrile; control of pruritis
Antivirals—Acyclovir within 24 hours after rash onset
Consider—patients over 12 years old, secondary contacts, patients with chronic cutaneous and cardiopulmonary disease, and children on long-term salicylate therapy
High dose IV antivirals—for immunocompromised patients, pregnancy (3rd trimester), extracutaneous disease
Prophylaxis for profoundly immunosuppresed patients
Postherpetic neuralgia—gabapentin, lidocaine patches
Tricyclic antidepressants, opioids, capsaicin cream
Epidural injection of steroids and anesthetics

35. VZV—Prognosis and Prevention
Varicella—duration usually 2 weeks or less; fatalites rare
Zoster—2-6 weeks; greater antibody response
Ophthalmic involvement—periodic exams
Screen healthcare workers and vaccinate if negative
Workers with zoster should receive antiviral agents during 1st 72 hours of disease and stay away from work until lesions are crusted
Isolate patients with active VZV from negative contacts

36. Varicella Vaccination
Universal childhood vaccination against varicella—98.1% effective when given after 13 months of age
1st dose months, 2nd dose 4-6 years
Avoid aspirin for at least 6 weeks
Seronegative individuals over 13 years old—2 doses of varicella vaccine 4-8 weeks apart
Consider vaccination for HIV + adolescents and adults with CD4 200 cells/mcL or higher
Also other selected immunocompromised pts (see text)
Varicella incidence decreased 67%-87% due to vaccination
Postexposure vaccination recommended for unvaccinated persons without other evidence of immunity
Varicella Zoster immunoglobulin—consider for susceptible pts who cannot receive vaccine

37. Zoster Vaccination
Live attenuated VZV vaccine—for patients 60 and older
Reduces incidence of postherpetic neuralgia by 67%
Reduces incidence of herpes zoster by 51%
Should not co-administer with pneumonia vaccine

38. Rabies

39. Rabies Viral encephalitis transmitted by infected saliva
50, ,000 deaths/year globally
In US—dog rabies has almost disappeared, but wildlife rabies has greatly increased
Incubation—10 days to years (usually 3-7 weeks)
Inoculation site  nerves  brain  efferent nerves  salivary glands
Forms cytoplasmic inclusion bodies
Almost uniformly fatal

40. Rabies Symptoms History of animal bite (may not notice bat bite)
Pain (at bite location), fever, malaise, headache, nausea, vomiting
Aerophobia and sensitivity to temperature change
Percussion myoedema
10 days after prodrome—CNS stage
Encephalitic—”furious”—80%--classic rabies symptoms
Paralytic—”dumb”—20%--acute ascending paralysis
Progresses to coma, ANS dysfunction, and death

41. Rabies Diagnosis Bitten animals that appear well—quarantine 10 days
Ill or dead animals—test for rabies
If animal cannot be examined—presume that raccoons, skunks, bats, foxes, bats and foxes are rabid
Direct fluoroscent antibody testing—skin material from posterior neck—60-80% sensitivity
Definitive diagnostic assays—
RT-PCR
nucleic acid sequence-based amplification
direct rapid immunohistochemical test
viral isolation from CSF or saliva

42. Rabies Treatment Intensive care—airway, oxygenation, seizure control
Universal precautions
Postexposure prophlaxis given prior to symptoms—nearly 100% successful in disease prevention
Once symptoms have appeared, death almost inevitably occurs after 7 days, usually from respiratory failure

43. Rabies—Prevention
Immunization of household dogs, cats, and patients with significant animal exposure
Cleansing, debridement, and flushing of wounds
Do not suture animal bite wounds
Decision to treat with immune globulin or antiserum— varies with circumstances of bite
Consult with state and local health departments
Give treatment as promptly as possible if indicated
Read—when to admit, when to refer

44. Questions?